Carrier composition

ABSTRACT

A carrier composition of the present invention comprises a phosphate compound of an electron transfer agent and a relatively high concentration of a polar protic solvent. A biologically active compound may be formulated with a carrier composition of the present invention to provide a formulation.

TECHNICAL FIELD

The present invention relates to carrier compositions for delivery ofbiologically active compounds.

BACKGROUND

In this specification where a document, act or item of knowledge isreferred to or discussed, this reference or discussion is not anadmission that the document, act or item of knowledge or any combinationthereof was at the priority date, publicly available, known to thepublic, part of common general knowledge; or known to be relevant to anattempt to solve any problem with which this specification is concerned.

Drug delivery is the method or process of administering a pharmaceuticalcompound to achieve a therapeutic effect in humans and animals.

Drug delivery technologies have been developed to improvebioavailability, safety, duration, onset or release, of thepharmaceutical compound. When developing drug delivery technologies,problems likely to be encountered include compatibility of the drugdelivery system and the pharmaceutical compound, maintaining an adequateand effective duration, potential for side effects, and meeting patientconvenience and compliance. As a consequence, many drug deliverytechnologies fall short of desired improvements and requirements.

Accordingly, there is still a need for alternate drug delivery systemswhich effectively deliver drugs.

SUMMARY

It has surprisingly been found that a carrier composition comprising aphosphate compound of an electron transfer agent and a relatively highconcentration of a polar protic solvent can improve the delivery of abiological active compound.

According to a first aspect of the invention there is provided a carriercomposition for delivery of a biologically active compound comprising aphosphate compound of an electron transfer agent and a polar proticsolvent, wherein the polar protic solvent concentration is greater than50% w/w of the total concentration of the carrier composition. There isalso provided use of a phosphate compound of an electron transfer agentand a polar protic solvent in the manufacture of the carriercomposition.

There is further provided a process for the preparation of the carriercomposition which comprises the step of combining a phosphate compoundof an electron transfer agent and a polar protic solvent until completehomogenisation is achieved.

The polar protic solvent concentration is within the range of preferablyabout 60% w/w to about 90% w/w, more preferably about 65% w/w to about85% w/w, most preferably about 70% w/w to about 80% w/w. In somecircumstances, a suitable range may be about 50% w/w to about 60% w/w,about 60% w/w to about 70% w/w or about 80% w/w to about 90% w/w.

In one embodiment the polar protic solvent is an acyclic alcohol. AC₂-C₃ acyclic alcohol is preferred, and ethanol and propanol are mostpreferred.

The electron transfer agent may be an antioxidant or a derivatisedcompound thereof. In a preferred embodiment the electron transfer agentis a hydroxy chroman, preferably a tocol such as tocopherol ortocotrienol.

Phosphate compounds of tocopherol may be selected from the groupconsisting of mono-(tocopheryl) phosphate, mono-(tocopheryl) phosphatemonosodium salt, mono-(tocopheryl) phosphate monopotassium salt,mono-(tocopheryl) phosphate disodium salt, mono-(tocopheryl) phosphatedipotassium salt, di-(tocopheryl) phosphate, di-(tocopheryl) phosphatemonosodium salt, di-(tocopheryl) phosphate monopotassium salt, or amixture thereof.

When the carrier composition comprises a mixture of a mono-(tocopheryl)phosphate to a di-(tocopheryl) phosphate, the ratio is preferably atleast 2:1, more preferably within the range of about 4:1 to about 1:4,most preferably within the range of about 6:4 to about 8:2. In preferredembodiments the ratio is about 6:4 or about 8:2.

The carrier composition comprises a phosphate compound of an electrontransfer agent in an amount within the range of preferably about 0.01%w/w to about 20% w/w, more preferably about 0.01% w/w to about 10% w/w,most preferably about 0.01% w/w to about 5% w/w or about 0.01% w/w toabout 1% w/w of the total concentration of the carrier composition. Inone embodiment the carrier composition comprises a phosphate compound ofan electron transfer agent in an amount within the range of about 0.01%w/w to about 2% w/w, preferably about 0.05% w/w, about 0.1% w/w or about1% w/w. In a further embodiment, a range of about 5% w/w to about 10%w/w or about 10% w/w to about 15% w/w may be used.

In a second aspect of the invention there is provided a formulationcomprising the carrier composition and a biologically active compound.

There is also provided a process for the preparation of the formulationwhich comprises the step of adding a biologically active compound to thecarrier composition.

In one embodiment, the biologically active compound is lipophilic havinga log P value within the range of about 1 to about 5. The biologicallyactive compound also preferably has a relatively low molecular mass anda relatively low melting point.

A biologically active compound may be present in an amount of up toabout 30% w/w of the total concentration of the carrier composition.

In a third aspect of the invention there is provided use of the carriercomposition to improve the delivery of a biologically active compoundformulated with the carrier corn position.

There is also provided use of the carrier composition to alter A.D.M.E.properties of a biologically active compound.

There is further provided use of the carrier composition to improve thebioavailability of a biologically active compound in a subject.

In a fourth aspect of the invention there is provided a method fortreating a subject for a pathological condition which comprisesadministering an effective amount of a biologically active compound inthe carrier composition. The pathological conditions include those thatcan be treated by the biologically active compound formulated with thecarrier corn position.

DETAILED DESCRIPTION

A carrier composition of the present invention comprises a phosphatecompound of an electron transfer agent and a relatively highconcentration of a polar protic solvent. A biologically active compoundmay be formulated with a carrier composition of the present invention toprovide a formulation.

In this specification, except where the context requires otherwise, thewords “comprise”, “comprises”, and “comprising” mean “include”,“includes”, and “including” respectively, i.e. when the invention isdescribed or defined as comprising specified features, variousembodiments of the same invention may also include additional features.

Phosphate Compound of an Electron Transfer Agent

The term “electron transfer agent” refers to a compound that may bephosphorylated and which, in the non-phosphorylated form, can accept anelectron to generate a relatively stable molecular radical or can accepttwo electrons to allow the compound to participate in a reversible redoxsystem. Examples of electron transfer agents include antioxidants andderivatives thereof.

The term “antioxidant” refers to a molecule capable of slowing orpreventing the oxidation of other molecules. Oxidation is a chemicalreaction that transfers electrons from a substance to an oxidizingagent. Oxidation reactions can produce free radicals, which start chainreactions that damage cells. Antioxidants terminate these chainreactions by removing free radical intermediates, and inhibit otheroxidation reactions by being oxidized themselves. As a result,antioxidants are often reducing agents.

Antioxidants are generally classified into two broad divisions,depending on whether they are soluble in water (hydrophilic) or inlipids (hydrophobic). Ascorbic acid (vitamin C) is an example of a watersoluble antioxidant. Carotenes, tocopherol (Vitamin E), retinol (VitaminA), ubiquinol (the reduced form of coenzyme Q) and calciferol (VitaminD) are examples of lipid soluble antioxidants.

Carotenes are carotenoids containing no oxygen. Carotenoids are based oncarotenes with one or more hydrogen atoms substituted by a hydroxylgroup and/or some pairs of hydrogen atoms are substituted by oxygenatoms. The term “hydroxy carotenoids” refers to carotenes substitutedwith one or more hydroxyl groups. Cryptoxanthin is an example of ahydroxy carotenoid: it is closely related to beta-carotene with only theaddition of a hydroxyl group.

Vitamin E exists in eight different forms, namely four tocopherols andfour tocotrienols. All feature a chroman ring, with a hydroxyl groupthat can donate a hydrogen atom to reduce free radicals and ahydrophobic side chain which allows for penetration into biologicalmembranes. Such derivatives of Vitamin E may be classified as “hydroxychromans”. Both tocopherols and tocotrienols occur in alpha, beta, gammaand delta forms, determined by the number and location of methyl groupson the chroman ring. The tocotrienols differ from the analogoustocopherols by the presence of three double bonds in the hydrophobicside chain. The various forms of Vitamin E are shown by Formula (I):

(I) R₁ R₂ R₃ α-tocopherol CH₃ CH₃ CH₃ α-tocotrienol CH₃ CH₃ CH₃β-tocopherol CH₃ H CH₃ β-tocotrienol CH₃ H CH₃ γ-tocopherol H CH₃ CH₃γ-tocotrienol H CH₃ CH₃ δ-tocopherol H H CH₃ δ-tocotrienol H H CH₃

Retinol belongs to the family of chemical compounds known as retinoids.There are three generations of retinoids. First generation retinoidsinclude retinol, retinal, tretinoin (retinoic acid, Retin-A),isotretinoin and alitretinoin. Second generation retinoids includeetretinate and its metabolite acitretin. Third generation retinoidsinclude tazarotene, bexarotene and adapalene.

Ubiquinol is a benzoquinol and is the reduced form of ubiquinone(coenzyme Q₁₀).

Calciferol (Vitamin D) comes in several forms. The two major forms arevitamin D₂ (e.g. ergocalciferol) and vitamin D₃ (e.g. calcitriol,cholecalciferol). The other forms include vitamin D₁ (molecular compoundof ergocalciferol with lumisterol, 1:1), vitamin D₄(22-dihydroergocalciferol) and vitamin D5 (sitocalciferol, made from7-dehydrositosterol).

Any antioxidant or derivative thereof described herein would be suitablefor the present invention. Preferred antioxidants and derivativesthereof are selected from the group consisting of carotenoids, hydroxychromans, carotenoids, retinoids, benzoquinols and calcitriols. Hydroxychromans are preferred. Tocols such as a tocopherol, in any form, ismost preferred.

The term “phosphate compound” refers to a phosphorylated compound, wherea covalent bond is formed between an oxygen atom (typically originatingfrom a hydroxyl group) of the compound and the phosphorous atom of aphosphate group (PO₄): in this context, the compound is an electrontransfer agent.

The phosphate compound may be a phosphate mono-ester, phosphatedi-ester, phosphate tri-ester, pyrophosphate mono-ester, pyrophosphatedi-ester, or a salt or derivative thereof, or a mixture thereof. The di-and tri-esters may comprise the same electron transfer agent ordifferent electron transfer agents.

The “salts” include metal salts such as alkali or alkaline earth metalsalts, for example sodium, magnesium, potassium and calcium salts.Sodium and potassium salts are preferred.

The “derivatives” include phosphate compounds where one or morephosphate protons are replaced by a substituent. Some non-limitingexamples of derivatives include phosphatidyl derivatives where aphosphate proton is substituted with an amino-alkyl group, sugarderivatives where a phosphate proton is substituted with a sugar such asglucose.

The term “amino-alkyl group” refers to a group comprising an amino(—NH₂) group and an alkyl group. The term “alkyl” refers to straightchain, branched chain or cyclic hydrocarbon groups having from 1 to 8carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, heptyl, andoctyl. Phosphatidyl choline derivatives are most preferred.

When the electron transfer agent is tocopherol, for example, thephosphate compounds of tocopherol may be selected from the groupconsisting of mono-(tocopheryl) phosphate, mono-(tocopheryl) phosphatemonosodium salt, mono-(tocopheryl) phosphate monopotassium salt,mono-(tocopheryl) phosphate disodium salt, mono-(tocopheryl) phosphatedipotassium salt, di-(tocopheryl) phosphate, di-(tocopheryl) phosphatemonosodium salt, di-(tocopheryl) phosphate monopotassium salt, or amixture thereof. These phosphate compounds may be derived from thealpha, beta, gamma or delta form of tocopherol, or a combinationthereof.

When the carrier composition contains a mixture of a mono-phosphateester and a di-phosphate ester, for example a mono-(tocopheryl)phosphate and di-(tocopheryl) phosphate, the ratio is preferably atleast 2:1, more preferably within the range of about 4:1 to about 1:4,most preferably within the range of about 6:4 to about 8:2. The ratiomay be about 6:4 or about 8:2.

The carrier composition comprises a phosphate compound of an electrontransfer agent in an amount within the range of preferably about 0.01%w/w to about 20% w/w, more preferably about 0.01% w/w to about 10% w/w,most preferably about 0.01% w/w to about 5% w/w or about 0.01% w/w toabout 1% w/w of the total concentration of the carrier composition. Thecarrier composition may comprise a phosphate compound of an electrontransfer agent in an amount within the range of about 0.01% w/w to about2% w/w, preferably about 0.05% w/w, about 0.1% w/w or about 1% w/w. In afurther embodiment, a range of about 5% w/w to about 10% w/w or about10% w/w to about 15% w/w may be suitable.

Polar Protic Solvent

Organic solvents may be grouped as non-polar or polar aprotic solvents,and polar protic solvents.

The organic solvent of the present invention is a polar protic solvent.A “protic solvent” is a solvent that has a hydrogen atom bound to anoxygen atom or a nitrogen atom as in a hydroxyl group or an amine group,respectively. More generally, any molecular solvent which contains ahydrogen ion capable of dissociation may be considered a protic solvent.Conversely, an “aprotic solvent” cannot donate hydrogen ions.

The polar protic solvent may be an acyclic alcohol, alkyl ester, ketoneor nitrile. The acyclic alcohol may be selected from the groupconsisting of C₁-C₄ acyclic alcohols including polyols, polymers andderivatives (e.g. esters, alkyl esters, ethers) thereof. Some examplesof these include ethanol, n-propanol, isopropanol, glycols such aspropylene glycol, polyethylene glycol (e.g. PEG400), diethylene glycolmonoethylether and ethyl acetate. The ketone may be selected from thegroup consisting of methyl isobutyl ketone and acetone. The nitrile maybe acetonitrile.

The carrier composition may comprise only one polar protic solvent;however, a combination of polar protic solvents may also be used. Forthe avoidance of any doubt, it is to be noted that the singular forms“a”, “an” and “the” as used herein for any feature should be read asencompassing plural forms, unless the context clearly indicatesotherwise.

The carrier composition has a relatively high polar protic solventconcentration. The polar protic solvent concentration is within therange of preferably about 60% w/w to about 90% w/w, more preferablyabout 65% w/w to about 85% w/w, most preferably about 70% w/w to about80% w/w. The polar protic solvent concentration may be about 70% w/w orabout 80% w/w. In some circumstances a suitable range of polar proticsolvent concentration may be about 50% w/w to about 60% w/w, about 60%w/w to about 70% w/w or about 80% w/w to about 90% w/w.

Biologically Active Compound

The term “biologically active compound” refers to any chemical substancethat has a biological effect in humans or animals for medical,therapeutic, cosmetic and veterinary purposes, and encompassespharmaceuticals including drugs, cosmeceuticals, nutraceuticals, andnutritional agents. It will be appreciated that some of biologicallyactive compounds can be classified in more than one of these classes.

A wide range of biologically active compounds may be delivered with acarrier composition of the present invention. Preferably, thebiologically active compound is lipophilic, and has a relatively lowmolecular mass and a relatively low melting point.

The term “lipophilicity” refers to the ability of a chemical compound todissolve in fats, oils, lipids, and non-polar solvents such as hexane ortoluene. The lipophilicity of a biologically active compound may beassessed by its octanol/water partitioning coefficient (log P value),which is believed to approximate membrane permeability. Transdermallypermeable biologically active compounds are likely to have a log P valuebetween about 2.5 to about 3.5. It has been found that biologicallyactive compounds having a log P value within this range and biologicallyactive compounds having a log P value outside this range (either aboveor below) formulated with a carrier composition of the present inventionare more transdermally permeable, that is, biologically active compoundshaving a log P value within the range of about 1 to about 5. Therefore,the biologically active compound may have a log P value within the rangeof about 1 to about 2.5, within the range of about 2.5 and about 3.5,and within the range of about 3.5 to about 5.

Not wishing to be bound by theory, it is believed that a carriercomposition of the present invention can alter one or more A.D.M.E.(Absorption, Distribution, Metabolism, and Excretion) properties of abiological active compound to improve the delivery of the biologicalactive compound. To be an effective biological active compound, thebiological active compound not only must be active against a target, butalso possess the appropriate A.D.M.E. properties necessary to make itsuitable for use as a biological active compound.

A “relatively low molecular mass” refers to a molecular mass of lessthan about 1000 Daltons, preferably less than about 500 Daltons, morepreferably within the range of about 200 Daltons to about 300 Daltons.

A “relatively low melting point” refers to a melting point of less thanabout 400° C.

A wide range of biologically active compounds may be delivered with thecarrier composition of the present invention. Examples include, but arenot limited to cardiovascular drugs, in particular antihypertensiveagents (e.g. calcium channel blockers (or calcium antagonists)) andantiarrhythmic agents; congestive heart-failure pharmaceuticals;inotropic agents; vasodilators; ACE inhibitors; diuretics; carbonicanhydrase inhibitors; cardiac glycosides; phosphodiesterase inhibitors;α blockers; β blockers; sodium channel blockers; potassium channelblockers; β-adrenergic agonists; platelet inhibitors; angiotensin IIantagonists; anticoagulants; thrombolytic agents; treatments forbleeding; treatments for anaemia; thrombin inhibitors; antiparasiticagents; antibacterial agents; antiinflammatory agents, in particularnon-steroidal antiinflammatory agents (NSAIDs), more particularly COX-2inhibitors; steroidal antiinflammatory agents; prophylacticantiinflammatory agents; antiglaucoma agents; mast cell stabilisers;mydriatics; agents affecting the respiratory system; allergic rhinitispharmaceuticals; alpha-adrenergic agonists; corticosteroids; chronicobstructive pulmonary disease pharmaceuticals; xanthine-oxidaseinhibitors; antiarthritis agents; gout treatments; autacoids andautacoid antagonists; antimycobacterial agents; antifungal agents;antiprotozoal agents; anthelmintic agents; antiviral agents especiallyfor respiratory , herpes, cyto-megalovirus, human immunodeficiency virusand hepatitis infections; treatments for leukemia and kaposi's sarcoma;pain management agents in particular anaesthetics and analgesics,opioids including opioid receptor agonists, opioid receptor partialagonists, opioid antagonist or opioid receptor mixedagonist-antagonists; neuroleptics; sympathomimetic pharmaceuticals;adrenergic agonists; drugs affecting neurotransmitter uptake or release;anticholinergic pharmaceuticals; antihaemorrhoid treatments; agents toprevent or treat radiation or chemotherapeutic effects; liopgenisisdrugs; fat reducing treatments; antiobesity agents such as lipaseinhibitors; sympathomimetic agents; treatments for gastric ulcers andinflammation such as proton pump inhibitors; prostaglandins; VEGFinhibitors; antihyperlipidemic agents, in particular statins; drugs thataffect the central nervous system (CNS) such as antipsychotic,antiepileptic and antiseizure drugs (anticonvulsants), psychoactivedrugs, stimulants, antianxiety and hypnotic drugs, antidepressant drugs;antiparkinson's pharmaceuticals; hormones and fragments thereof such assex hormones; growth hormone antagonists; gonadotropin releasinghormones and analogues thereof; steroid hormones and their antagonists;selective estrogen modulators; growth factors; antidiabeticpharmaceuticals such as hypoglycaemic agents; H1, H2, H3 and H4antihistamines; agents used to treat migraine headaches; asthmapharmaceuticals; cholinergic antagonists; glucocorticoids; androgens;antiandrogens; inhibitors of adrenocorticoid biosynthesis;

osteoporosis treatments such as biphosphonates; antithyroidpharmaceuticals; suncreens, sun protectants and filters; cytokineagonists; cytokine antagonists; anticancer drugs; antialzheimer drugs;HMGCoA reductase inhibitors; fibrates; cholesterol absorptioninhibitors; HDL cholesterol elevating agents; triglyceride reducingagents; antiageing or antiwrinkle agents; antibacterial agents; antiacneagents; antioxidants; hair treatments and skin whitening agents; smallmolecule therapeutic agents for the treatment, or prevention of humanand animal diseases such as allergy/asthma, arthritis, cancer, diabetes,growth impairment, cardiovascular diseases, inflammation, immunologicaldisorders, baldness, pain, ophthalmological diseases, epilepsy,gynaecological disorders, CNS diseases, viral infections, bacterialinfections, parasitic infections, GI diseases, obesity, and haemologicaldiseases.

A person skilled in the art of the invention would be able to determinewhether or not a particular biologically active compound would besuitable for use with the carrier composition of the present invention.Some specific non-limiting examples of suitable biologically activecompounds include:

Anaesthetics:

including amino-ester and amino-amide anaesthetics such as benzocaine,chloroprocaine, cocaine, reserpine, guanethidine, cyclomethycaine,dimethocaine/larocaine, propoxycaine, procaine/novocaine, proparacaine,tetracaine/amethocaine; articaine, bupivacaine, carticaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, piperocaine, prilocaine, ropivacaine,trimecaine, propofol, halothane, enflurane barbiturates,benzodiazepines, neostigmine and ketamine

Alkylating Agents;

including carmustine, cyclophosphamide, ifosfamide, streptozotocin andmechlorethamine

Calcium Channel Blockers:

including amlodipine, aranidipine, azelnidipine, barnidipine,benidipine, cilnidipine, clevidipine, cronidipine, darodipine,dexniguldipine, efonidipine, elnadipine, elgodipine, felodipine,flordipine, furnidipine, iganidipine, isradipine, lacidipine,lemildipine, lercanidipine, manidipine, mesuldipine, nicardipine,nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, olradipine, oxodipine, palonidipine, pranidipine,sagandipine, sornidipine, teludipine, tiamdipine, trombodipine,watanidipine, verapamil, gallopamil, benzothiazepine, diltiazem,mibefradil, bepridil, fluspirilene and fendiline

Antiarrhythmic and Antiangina Agents:

including amiodarone, disopyramide, flecainide acetate, quinidinesulphate, nitroglycerine, ranolazine, amiodarone, isosorbide andalteplase

Antibacterial, Antibiotic and Antiacne Agents:

including amoxicillin, ampicillin, azithromycin, benethamine penicillin,bleomycin, benzoyl peroxide, cinoxacin, chloramphenicol, daunorubicin,plicamycin, fluoroquinolones, ciprofloxacin, clarithromycin,clindamycin, clindesse, clofazimine, chlorohexidine gluconate,cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide,imipenem, indomethacin, lymocycline, minocycline, nalidixic acid,nitrofurantoin, penicillin, rifampicin, spiramycin, sodiumsulfacetamide, sulphabenzamide, sulphadoxine, sulphamerazine,sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, cephalexin, cefolinir, triclosan,ofloxacin, vancocin, glyburide, mupirocin, cefprozil, cefuroxime axetil,norfloxacin, isoniazid, lupulone, D-penicillamine, levofloxacin,gatifoxacin, and trimethoprim

Anticancer:

including doxorubicin, 6-thioguanine, paclitaxel, docetaxel,camptothecin, megestrol acetate, navelbine, cytarabine, fludarabine,6-mercaptopurine, 5-fluorouracil, teniposide, vinblastine, vincristine,cisplatin, colchicine, carboplatin, procarbazine and etopside

Antidepressants, Antipsychotics and Antianxiety:

including alprazolam, amoxapine, bentazepam, bromazepam, clorazipine,clobazam, clotiazepam, diazepam, lorazepam, flunitrazepam, flurazepam,lormetazepam, medazepam, nitrazepam, oxazepam, temazepam, maprotiline,mianserin, nortriptyline, risperidone, sertraline, trazodone,baloperidol, trimipramine maleate fluoxetine, ondansetron, midazolam,chlorpromazine, haloperidol, triazolam, clozapine, fluopromazine,fluphenazine decanoate, fluanisone, perphenazine, pimozide,prochlorperazine, sulpiride, thioridazine, paroxitine, citalopram,bupropion, phenelzine, olanzapine, divalproex sodium and venlafaxine

Opioids:

including opioid receptor agonists and antagonists, compounds whichexhibit mixed agonistantagonist activity and compounds which exhibitpartial agonist activity, including morphine, depomorphine, etorphine,diacetylmorphine, hydromorphone, oxymorphone, levorphanol, methadone,levomethadyl, meperidine, fentanyl, sufentanyl, alfentanil, codeine,hydrocodone, oxycodone, thebaine, desomorphine, nicomorphine,dipropanoylmorphine, benzylmorphine, ethylmorphine, pethidine,methadone, tramadol, dextropropoxyphene;

naloxone and naltrexone; buprenorphine, nalbuphine, butorphanol,pentazocine and ethylketocyclazocine

Tricyclics:

including azothiopine, amitriptyline, famotidine, promethazine,paroxatine, oxcarbazapine and mertazapine

Antidiabetics:

including acetohexamide, chlorpropamide, glibenclaraide, gliclazide,glipizide, metformin, tolazamide, glyburide, glimepiride and tolbutamide

Antiepileptics: including beclamide, carbamazepine, gapapentin,tiagabine, vigabatrin, topiramate, clonazepam, ethotoin, methoin,methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione,phenacemide, phenobarbitone, phenyloin, phensuximide, primidone,sulthiamine, phenytoin sodium, nirofurantoin monohydrate, gabapentin,lamotrigine, zonisamide, ethosuximide and valproic acid

Hypnotics/Sedatives and Muscle Relaxants:

including zolpidem tartrate, amylobarbitone, barbitone, butobarbitone,pentobarbitone, brotizolam, carbromal, chlordiazepoxide,chlormethiazole, ethinamate, meprobamate, methaqualome, cyclobenzaprene,cyclobenzaprine, tizanidine, baclofen, butalbital, zopiclone,atracurium, tubocurarine and phenobarbital

Antifungal, Antiprotazoal and Antiparasitic Agents:

including amphotericin, butoconazole nitrate, clotrimazole, econazolenitrate, fluconazole, flucytosine, griseofulvin, itraconazole,ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate,terconazole, tioconazole and undecenoic acid; benznidazole, clioquinol,decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide,furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole,terbinafine, clotrimazole, chloroquine, mefloquine, itraconazole,Pyrimethamine, praziquantel, quinacrine, mebendazole and tinidazole

Antihypertensive and Cardiac Therapeutic Agents:

including candesartan, hydralazine, clonidine, triamterene, felodipine,gemfibrozil, fenofibrate, nifedical, prazosin, mecamylamine, doxazosin,dobutamine and cilexetil

Antimigraine Agents:

including dihydroergotamine mesylate, ergotamine tartrate, methysergidemaleate, pizotifen maleate and sumatriptan succinate

Antimuscarinic Agents:

including atropine, benzhexol, biperiden, ethopropazine, hyoscyamine,mepenzolate bromide, oxybutynin, oxyphencylcimine and tropicamide

Antineoplastic Agents (or Immunosuppressants):

including aminoglutethimide, amsacrine, azathioprine, busulphan,chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide,lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitozantrone, procarbazine, tamoxifen citrate, testolactone, tacrolimus,mercaptopurine and sirolimus

Antiparkinsonian Agents:

including bromocriptine mesylate, levodopa, tolcapone, ropinirole,bromocriptine, hypoglycaemic agents such as sulfonylureas, biguanides,a-glucosidase inhibitors, thaiazolidinediones, cabergoline, carbidopaand lysuride maleate

Antithyroid Agents:

including carbimazole and propylthiouracil

Antiviral Drugs:

including amantadine, retinovir, cidofovir, acyclovir, famciclovir,ribavirin, amprenavir, indinavirm, rimantadine and efavirenz,penciclovir, ganciclovir, vidarabine, abacavir, adefovir, apmrenavir,delavirdine, didanosine, stavudine, zalcitabine, zidovudine, enfuvirtideand interferon

Cardiac Inotropic Agents:

including amrinone, milrinone, digitoxin, digoxin, enoximone, lanatosideC and medigoxin

Hypo and Hyper Lipidemic Agents:

including fenofibrate, clofibrate, probucol, ezetimibe and torcetrapib

Antiinflammatory:

including meoxicam, triamcinolone, cromolyn, nedocromil,hydroxychloroquine, montelukast, zileuton, zafirlukast and meloxicam

Antihistamine:

including fexofenadine, chloral hydrate, hydroxyzine, promethazine,cetirazine, cimetidine, clyclizine, meclizine, dimenhydrinate,loratadine, nizatadine and promethazine

Antiulcer:

including omeprazole, lansoprazole, pantoprazole and ranitidine

Diuretics:

including hydrochlorothiazide, amiloride, acetazolamide, furosemide andtorsemide

NSAIDs:

including arylalkanoic acid sub-group of class which includesdiclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac,indometacin, indometacin farnesil, nabumetone, oxametacin,proglumetacin, sulindac and tolmetin; 2-arylpropionic acid (profens)sub-group of class which includes alminoprofen, benoxaprofen, carprofen,dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac,loxoprofen, miroprofen, naproxen, oxaprozin, pirprofen, suprofen,tarenflurbil and tiaprofenic acid; and N-arylanthranilic acid (fenamicacid) sub-group of class which includes flufenamic acid, meclofenamicacid, mefenamic acid and tolfenamic acid; tromethamine, celecoxib,nepafenac, aspirin, rofecoxib, naproxen, sulindac, piroxicam,pheylbutazone, tolmetin, indomethacin, acetominophen (paracetamol),tramadol and propoxyphene

Retinoids:

including first generation retinoids such as retinol, retinal, tretinoin(retinoic acid, Retin-A), isotretinoin and alitretinoin; secondgeneration retinoids such as etretinate and its metabolite acitretin;third generation retinoids such as tazarotene, bexarotene and adapalene

Hormones and Steroids:

including adrenocorticotrophic hormone (ACTH), antidiruetic hormone(vasopressin), atrial-nartreuretic factor (ANF), beclomethasone,cortisone, scopolamine, dopamine, epinephrine, catecholamines,cholecystokinin, clomiphene citrate, danazol, dexamethasone,diethylstilbestrol (DES), ethinyl estradiol, fludrocortison,finasteride, follicle stimulating hormone, gastrin, hydroxyprogesterone,leptin, luteinizing hormone, medroxyprogesterone acetate, mestranol,quinestrol, methyltestosterone, nandrolone, norethindrone,norethisterone, norgestrel, estradiol, conjugated oestrogens,oxandrolone, oxytocin, prednisone, progesterone, prolactin,protogalndins, somatostatin, stanozolol, stibestrol, thyroxine,prednisolone phosphate, triamcinolone, mifepristone acetonide,budesonide, levothyroxine, testosterone, testosterone cypionate,fluoxymesterone, flutamide, mometasone furoate, cyproterone,fluromethalone, goserelin, leuprolide, calcitonin, halobetasol,hydrocortisol and tibolone

Statins and Derivatives:

including atorvastatin, fluvastatin, lovastatin, nystatin, rosuvastatin,pravastatin, orlistat and simvastatin

Stimulants: including amphetamine, phentermine, tyramine, ephedrine,metaraminol, phenylephrine, dexamphetamine, dexfenfluramine,fenfluramine, nicotine, caffeine and mazindol

Vasocontrictors:

including desmopressin

Vasodilitors:

including carvedilol, terazosin, phentolamine and menthol

Antialzheimers:

including levetiracetam, levitiracetam and donepezil

ACE Inhibitors:

including benzapril, enalapril, ramipril, fosinopril sodium, lisinopril,minoxidil, isosorbide, rampril and quinapril

Beta Adrenoreceptor Antogonists:

including atenolol, timolol, pindolol, propanolol hydrochloride,bisoprolol, esmolol, metoprolol succinate, metoprolol and metoprololtartrate

Angiotensin II Antagonists: including losartan

Platelet Inhibitors:

including abciximab, clopidrogel, tirofiban and aspirin

Alcohols and Phenols:

including tramadol, tramadol hydrochloride, allopurinol, calcitriol,cilostazol, soltalol, urasodiol bromperidol, droperidol, flupenthixoldecanoate, albuterol, albuterol sulphate, carisoprodol, chlobetasol,ropinirol, labetalol, and methocarbamol

Ketones and Esters:

including amioderone, fluticasone, spironolactone, prednisone,triazodone, desoximetasone, methyl prednisdone, benzonatate nabumetoneand buspirone

Antiemetics:

including metoclopramide

Ocular Treatments:

including dorzolamide, brimonidine, olopatadine, cyclopentolate,pilocarpine and echothiophate

Anticoagulant and Antithrombitic Agents:

including warfarin, enoxaparin and lepirudin

Treatments for Gout:

including probenecid and sulfinpyrazone

COPD and Asthma Treatments: including ipratropium

Treatments for Osteoporosis:

including raloxifene, pamidronate and risedronate.

Particularly preferred biologically active compounds include lidocaine,diclofenac, ketoralac, prilocaine, halobetasol, hydrocortisol andcombinations thereof.

It is to be understood that pharmaceutically acceptable derivatives ofbiologically active compounds are included within the scope of thepresent invention.

The term “pharmaceutically acceptable derivatives” includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, ethers, or any other derivative including prodrugs andmetabolites, which upon administration to a subject in need is capableof providing, directly or indirectly, a biologically active compound asotherwise described herein.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19, 1977. Examples of pharmaceuticallyacceptable nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid, or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, furnarate, glucoheptonate, glycerophosphate,gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate, and aryl sulfonate.

The term “pharmaceutically acceptable ester” refers to esters which arehydrolysed in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include formates, acetates, propionates, butyrates,acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the biologically active compounds which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of a subject with undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible, of the compounds of the invention. The term“prodrug” refers to compounds that are rapidly transformed in vivo toyield the parent compound of the above formula, for example byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987.

A biologically active compound may be present in an amount of up toabout 30% w/w of the total concentration of the carrier composition. Theamount of biologically active compound is preferably up to about 10%w/w, more preferably up to about 6% w/w, most preferably within therange of about 0.1% w/w to about 5% w/w.

The carrier composition improves the delivery of a biological activecompound by altering the A.D.M.E. properties of the biological activecompound. Not wishing to be bound by theory, it is believed that theA.D.M.E. properties of a biological active compound are altered becausethe combination of a phosphate compound of an electron transfer agentand a relatively high concentration of a polar protic solvent changesthe solubility of the biologically active compound in different barriers(skin, mucous membranes, muscle, and so on). This solubility changeaffects the residence time of the drug in these tissues and delays, orshortens, the time at which the drug will be introduced to theelimination phase. Accordingly, a carrier composition of the presentinvention can provide the advantage of:

-   -   reduced side effects (i.e. minimalising the unrequired systemic        effect);    -   restricting the biologically active compound distribution to        specific areas (e.g. drug-targeting);    -   improving patient compliance (e.g. less amount used, smaller        application);    -   improving aesthetic feeling (e.g. fast-drying); and    -   increasing duration of action and/or shorten onset.

A carrier composition of the present invention may also improve thebioavailability of a biologically active compound in a subject.

The present invention can also be used in a method for treating asubject for a pathological condition which comprises administering aneffective amount of a biologically active compound in a carriercomposition of the present invention. The pathological conditionsinclude those that can be treated by the biologically active compoundformulated with the carrier composition.

The term “subject” as used herein refers to any animal having symptomsassociated with or caused by a pathological condition, which requirestreatment with a biologically active compound. The animal may be amammal, preferably a human, or may be a non-human primate ornon-primates such as used in animal model testing. While it isparticularly contemplated that a formulation of the invention issuitable for use in medical treatment of humans, it is also applicableto veterinary treatment, including treatment of companion animals suchas dogs and cats, and domestic animals such as horses, ponies, donkeys,mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such asprimates, felids, canids, bovids, and ungulates.

Generally, the terms “treating”, “treatment” and the like are usedherein to mean affecting a subject, tissue or cell to obtain a desiredpharmacological and/or physiological effect. The effect may beprophylactic in terms of completely or partially preventing one or morepathological conditions, and/or may be therapeutic in terms of a partialor complete cure of one or more pathological conditions.

Routes of Administration

Routes of administration can broadly be divided into a three categoriesby effect, namely, “topical” where the desired effect is local, so thesubstance is applied directly where its action is desired, “enteral”where the desired effect is systemic (non-local) so the substance isgiven via the digestive tract, and “parenteral” where the desired effectis systemic, so the substance is given by routes other than thedigestive tract.

The U.S. Food and Drug Administration recognise 111 distinct routes ofadministration. The following is a non-limiting list of examples ofroutes of administration.

Examples of topical routes of administration having a local effectinclude epicutaneous (onto the skin) and intravitreal (onto the eye).

Examples of enteral routes of administration having a systemic(non-local) effect include any form of administration that involves anypart of the gastrointestinal tract, such as oral (into the mouth),intranasal (into the nose), rectal (into the rectum), and vaginal (intothe vagina).

Examples of parenteral routes of administration by injection, infusionor diffusion having a systemic effect include intravenous (into a vein),intraarterial (into an artery), intramuscular (into a muscle),intracardiac (into the heart), subcutaneous (under the skin),percutaneous (via needle-puncture into the skin), intradermal (into theskin itself), intrathecal (into the spinal canal), intraperitoneal(infusion or injection into the peritoneum), intravesical infusion(infusion into the urinary bladder), epidural (injection or infusioninto the epidural space), transdermal or transcutaneous (diffusionthrough the intact skin), transmucosal (diffusion through a mucousmembrane), insufflation (diffusion through the nose), inhalational(diffusion through the mouth), sublingual (under the tongue), and buccal(absorbed through cheek near gumline).

Formulations according to the present invention can be in any suitableadministration form (see, for example, Pharmaceutics and PharmacyPractice, J. B. Lippincott Company, Philadelphia, Pa., Banker andChalmers, eds., pages 238-250 (1982)). Examples of suitableadministration forms includes, but are not limited to, solutions,liquids, suspensions, gels, poultices, reservoir patches, and creams.The formulations may also be prepared and stored in one form anddelivered in another, for example the formulation may be stored inliquid form and delivered in the form of a foam. The formulations andcan be prepared by any methods well known in the art of pharmacy such asdescribed in Remington J. P., The Science and Practice of Pharmacy, ed.A. R. Gennaro, 20^(th) edition, Lippincott, Williams and WilkinsBaltimore, Md. (2000). Such methods include the step of bringing intoassociation the biologically active compound with the carrier, and then,if necessary, shaping the formulation into the desired product.

Preparation of a Carrier Composition

A carrier composition of the present invention may be prepared by avariety of techniques.

One method of preparing the carrier composition involves combining thecomponents of the carrier composition, in suitable quantities, withstirring, until complete homogenisation is achieved.

In a preferred method, a phosphate compound of an electron transferagent is combined with a polar protic solvent, and warmed at 40° C.until a solution is formed. An aqueous phase, usually of lower volume,is heated to 40° C. and then added drop wise to the solution to form thecarrier composition. Alternately in some circumstances the phosphatecompound of the electron transfer agent combined with the polar proticsolvent may be added dropwise to the aqueous phase. The final pH of thecarrier composition may be adjusted to improve stability, for example bythe addition of sodium hydroxide. The carrier composition is usually aclear to translucent solution.

Depending on the solubility and stability of the biologically activecompound, it may be dissolved in either the aqueous or solvent phase.

The carrier composition may optionally further comprise one or moreexcipients. A person skilled in the art of the invention wouldappreciate suitable excipients which could be included with a carriercomposition or a formulation of the present invention. The choice ofother excipients will depend on the characteristics of the biologicallyactive compound and the form of administration used. Examples of otherexcipients include additional solvents such as water, thickeners orgelling agents, surfactants, buffers, emollients, sweeteners,disintegrators, flavours, colours, fragrances, electrolytes, appearancemodifiers, film foaming polymers, propellants and the like. Suitablesweeteners include sucrose, lactose, glucose, aspartame or saccharin.Suitable disintegrators include corn starch, methylcellulose,polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable gelling agents include hydroxy propyl cellulose (H PC) andcarbopol. Suitable flavours include peppermint oil, oil of wintergreen,cherry, orange or raspberry flavouring. Suitable propellants includebutane, carbon dioxide, ethane, hydrochloroflurocarbons, isobutane,nitrogen, nitrous oxide, propane, dimethyl ether, isopentanol, pentaneand mixtures thereof such as Propellant A-46 (20% propane and 80%isobutane). The relatively high concentration of organic solvent mayavoid the need for a further preservative to be added; however ifconsidered necessary, suitable preservatives that may be added includesodium benzoate, methylparaben, propylparaben, and sodium bisulphite.The amount of excipient or excipients, if present, is preferably up toabout 10% w/w,

more preferably up to about 5% w/w, most preferably up to about 3% w/w,and even more preferably either 0.01-3% w/w or 0.1-1% w/w of the totalconcentration of the carrier composition.

The carrier composition and formulation according to the presentinvention have been found to be physically stable, have no particle sizelarger than 300 nm. There is also no spontaneous sol-gel transformation.

FIGURES

The examples will be described with reference to the accompanyingfigures in which:

FIG. 1 shows the transdermal delivery of formulations comprisingoxycodone in Franz cells in vitro;

FIGS. 2A and 2B show the relative behaviour of formulations comprisingoxycodone in a dose response;

FIG. 3 shows comparative skin deposition results of formulationscomprising lidocaine;

FIG. 4 shows comparative skin deposition results of formulationscomprising diclofenac; and

FIG. 5 shows comparative skin deposition results of formulationscomprising ketorolac.

EXAMPLES

Various embodiments/aspects of the present invention will now bedescribed with reference to the following non-limiting examples.

Example 1

Carrier compositions were prepared according to the preferred methoddescribed above.

Each of the five carrier compositions comprised 1% w/w of a mixture ofmono-(tocopheryl) phosphate and di-(tocopheryl) phosphate in a ratio of8:2 and water, and the following polar protic solvent concentrations:

% polar protic solvent (i) 50% w/v ethanol (ii) 60% w/v ethanol (iii)70% w/v ethanol (iv) 80% w/v ethanol (v) 90% w/v ethanol

Method for Thermal Cycling

The carrier compositions were refrigerated at about 5° C. forapproximately 12 hours, and then subjected to a temperature of about 30°C. for approximately 12 hours for 3 cycles. Between each change oftemperature the carrier compositions were left at room temperature for 3hours and observed for any turbidity and orecioitation.

Clarity of solution Precipitate (i) slightly turbid none (ii) clear none(iii) clear none (iv) clear none (v) clear none

Example 2

This example compares percutaneous oxycodone delivery in vitro using aformulation of the present invention (Formulation 2A) and a formulationwhich comprises a low polar protic solvent concentration (Formulation2B). Details of the each formulation are as follows:

Formulation 2A Components Amounts A mixture of mono-(tocopheryl)phosphate and 1% w/w di-(tocopheryl) phosphate in a ratio of 6:4Isopropanol 70% w/w  Oxycodone 5% w/w Molecular mass: 315.40 g/molMelting point: 218-220° C. Hydroxypropyl cellulose (HPC) H 1% w/w QSdH₂O

Formulation 2B Components Amounts A mixture of mono-(tocopheryl)phosphate and 2% w/w di-(tocopheryl) phosphate in a ratio of 7:3Isopropanol 10% w/w Ethanol 10% w/w Oxycodone 1.5% w/w Carbopol NF100.25% w/w QS dH₂O

Formulation 2A had a pH of 6. Formulation 2B had a pH of 6.4.

Method

Formulation 2A was prepared according to the preferred method describedabove. Formulation 2B was similarly prepared.

Full thickness rat abdominal skin was used in 12ml vertical Franzdiffusion cells (PermeGear, PA). Rats were killed by asphyxiation usingCO₂ gas and the abdominal area carefully shaved and excised. Allunderlying fat and connective tissue was removed. Skin was frozen flatbetween sheets of aluminium foil and stored at −20° C. until the morningof experimentation.

PBS was used in the Franz cells as the receptor solution (12ml) and theFranz cells had a surface area of 1.77cm². During experiments, the cellswere maintained at 32° C. Finite dosing (40 μl) was used to approximatethe conditions to be used in vivo. Receiver solutions were sampledregularly over 4 hours to determine the percutaneous oxycodoneabsorption and analysed using HPLC. The results are presented in FIG. 1.The results are the averages of n=8-10 diffusion cells conducted acrosstwo separate days. Bars represent SEM.

Results

It was found that Formulation 2A, which has a polar protic solventconcentration of 70% w/w, could maintain a concentration of oxycodone of5 % w/w. Formulation 2B, which has a polar protic solvent concentrationof 20% w/w on the other hand, could only maintain a maximumconcentration of oxycodone of 1.5% w/w.

Although both formulations were able to transdermally deliver oxycodone,the results show that, after 4 hours, approximately 130 μg of oxycodonewas delivered by Formulation 2A compared to approximately 18 μgdelivered by Formulation 2B.

The drying time for Formulation 2A led to a rapid rate of delivery (i.e.flux), in addition to the increased total amount. The linear flux (J) ofpercutaneous oxycodone absorption for Formulation 2A was 40 μg.h/cm²,whereas Formulation 2B had flux of 5.54 μg.h/cm2.

While both the increased flux and amount of oxycodone delivered may bepartially attributed to the increased oxycodone concentration (andsubsequent dose), the results show that Formulation 2A also had higherbioavailability. The percentage of oxycodone delivered from the totalapplied dose was approximately 8% with Formulation 2A compared to onlyapproximately 3% with Formulation 2B.

Conclusion

The formulation of the present invention (Formulation 2A) was capable ofan increased oxycodone concentration relative to Formulation 2B.Formulation 2A also showed better percutaneous oxycodone absorption,both with respect to the rate and total oxycodone delivered, andsuperior bioavailability.

Example 3

This example is a dose response study that compares the performance of aformulation of the present invention (Formulation 3A) and an aqueousformulation (Formulation 3B) to determine their relative behaviour in adose response. Details of the each formulation are as follows:

Formulation 3A Components Amounts A mixture of mono-(tocopheryl)phosphate and 1% w/w di-(tocopheryl) phosphate in a ratio of 6:4Isopropanol 70% w/w  Oxycodone 5% w/w Molecular mass: 315.40 g/molMelting point: 218-220° C. HPC H 1% w/w QS dH₂O

Formulation 3B Components Amounts A mixture of mono-(tocopheryl)phosphate 10.8% w/w  monosodium salt and di-(tocopheryl) phosphate in aratio of 2:1 Oxycodone•HCl 0.7% w/w Molecular mass: 351.83 g/mol Pemulen0.7% w/w QS dH₂O

Formulation 3A had a pH of 6. Formulation 38 had a pH of 8.

Method

Formulation 3A was prepared according to the preferred method describedabove. Formulation 3B was similarly prepared.

Full thickness rat abdominal skin was used in 12ml vertical Franzdiffusion cells (PermeGear, PA). Rats were killed by asphyxiation usingCO₂ gas and the abdominal area carefully shaved and excised. Allunderlying fat and connective tissue was removed. Skin was frozen flatbetween sheets of aluminium foil and stored at −20° C. until the morningof experimentation.

PBS was used in the Franz cells as the receptor solution (12 ml) and theFranz cells had a surface area of 1.77 cm². During experiments, thecells were maintained at 32° C. Finite dosing (20-60 μl) was used toapproximate the conditions to be used in vivo. Receiver solutions weresampled regularly over 4 hours to determine the percutaneous oxycodoneabsorption and analysed using HPLC. The results are presented in FIGS.2A and 2B.

Results

Formulation 3A had increased transdermal flux compared to Formulation3B. The use of a high polar protic solvent concentration (Formulation3A) allowed equivalent amounts of the preferred form of oxycodone (base;5% w/w) to be formulated.

With equivalent doses between 10-20 μl/cm², Formulation 3A deliveredtwice as much oxycodone as Formulation 3B, with both formulationsexhibiting a good dose response. At a dose of 30 μl/cm², no furtherincrease in transdermal delivery is seen with Formulation 3B. The doseresponse continues for Formulation 3A even at the highest dose of 30μl/cm².

Conclusion

This dose response study particularly shows that a formulation of thepresent invention (Formulation 3A) allows for wider dynamic range indose responses.

Example 4

This example compares the stability, skin deposition and otherproperties of a formulation of the present invention (Formulation 4A)and a formulation which comprises a low polar protic solventconcentration (Formulation 4B). Details of the each formulation are asfollows:

Formulation 4A Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 8:2Ethanol 80% w/w  Lidocaine base 5% w/w Molecular mass: 234.34 Meltingpoint: 68° C. Hydroxypropyl cellulose(GPHX grade, where G is the 3% w/wMolecular mass grade, PHX means pharmaceutical grade.) QS dH₂O

Formulation 4B Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 2:1Ethanol 30% w/w  Lidocaine base 1% w/w Molecular mass: 234.34 Meltingpoint: 68° C. Carbopol (CP934) 1% w/w QS dH₂O

Method

Formulation 4A was prepared according to the preferred method describedabove. Formulation 4B was similarly prepared.

Results

The results of a visual stability test showed that, after 3 days ofstorage, there were no physical changes noted with Formulation 4Awhereas a precipitate had formed with Formulation 4B.

After 4 hours of administration, Formulation 4A had a significant skindeposition (μg) compared to Formulation 4B, as shown in FIG. 3.

Conclusion

The results showed that a formulation of the present invention(Formulation 4A) was stable and had improved delivery compared toFormulation 4B.

Example 5

This example compares the stability, skin deposition and otherproperties of a formulation of the present invention (Formulation 5A)and a formulation which comprises a low polar protic solventconcentration (Formulation 5B). Details of the each formulation are asfollows:

Formulation 5A Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 6:4Isopropanol 70% w/w  Diclofenac diethylamine 2% w/w Hydroxypropylcellulose (GPHX grade, where G is the 3% w/w Molecular mass grade, PHXmeans pharmaceutical grade.) QS dH₂O

Formulation 5B Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 6:4Isopropanol 10% w/w Diclofenac diethylamine 1% w/w Hydroxypropylcellulose (GPHX grade, where G is the 0.6% w/w Molecular mass grade, PHXmeans pharmaceutical grade.) QS dH₂O

Method

Diclofenac Formulation 5A was prepared according to the preferred methoddescribed above. Formulation 5B was similarly prepared.

Results The results of a visual stability test showed that, after 3 daysof storage, there were no physical changes noted with Formulation 5Awhereas a precipitate had formed with Formulation 5B.

After 4 hours of administration, Formulation 5A had a significant skindeposition (μg) compared to Formulation 5B, as shown in FIG. 4. In FIG.4, Formulations 5A and 5B are also compared to the commerciallyavailable product comprising diclofenac Voltaren®.

Conclusion

The results showed that a formulation of the present invention(Formulation 5A) was stable and had improved delivery compared toFormulation 5B.

Example 6

This example compares the stability, skin permeation and otherproperties of a formulation of the present invention (Formulation 6A)and a formulation which comprises a low polar protic solventconcentration (Formulation 6B). Details of the each formulation are asfollows:

Formulation 6A Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 6:4Isopropanol 70% w/w  Ketorolac tromethamine 2% w/w Hydroxypropylcellulose (GPHX grade, where G is the 3% w/w Molecular mass grade, PHXmeans pharmaceutical grade) QS dH₂O

Formulation 6B Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 6:4Isopropanol 10% w/w Ketorolac tromethamine 2% w/w Hydroxypropylcellulose (GPHX grade, where G is the 0.6% w/w Molecular mass grade, PHXmeans pharmaceutical grade) QS dH₂O

Method

Formulation 6A was prepared according to the preferred method describedabove. Formulation 6B was similarly prepared.

A skin permeation test similar to that conducted for Example 2 was alsoconducted with the formulations.

Results

The results of a visual stability test showed that, after 3 days ofstorage, there were no physical changes noted with Formulation 6Awhereas a precipitate had formed with Formulation 6B.

After 4 hours of administration, Formulation 6A had a significant skindeposition (μg) compared to Formulation 6B, as shown in FIG. 5.

Conclusion

The results showed that a formulation of the present invention(Formulation 6A) was stable and had improved delivery compared toFormulation 6B.

Example 7

This example compares the stability and other properties of aformulation of the present invention (Formulation 7A) and a formulationwhich comprises a low polar protic solvent concentration (Formulation7B). Details of the each formulation are as follows:

Formulation 7A Components Amounts A mixture of mono-(toeopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 6:4Isopropanol 70% w/w  Felodipine 1% w/w QS dH₂O

Formulation 7B Components Amounts A mixture of mono-(tocopheryl)phosphate and di- 1% w/w (tocopheryl) phosphate in a ratio of 2:1Isopropanol 10% w/w  Felodipine 1% w/w Hydroxypropyl cellulose (GPHXgrade, where G is the 3% w/w Molecular mass grade, PHX meanspharmaceutical grade.) QS dH₂O

Method

Formulation 7A was prepared according to the preferred method describedabove. Formulation 7B was similarly prepared.

Results

The results of a visual stability test showed that, after 3 days ofstorage, there were no physical changes noted with Formulation 7Awhereas a precipitate had formed with Formulation 7B.

After 4 hours of administration, Formulation 7A had a significant skindeposition (μg) compared to Formulation 7B.

Conclusion

The results showed that a formulation of the present invention(Formulation 7A) was stable and had improved delivery compared toFormulation 7B.

It will be understood to persons skilled in the art of the inventionthat many modifications may be made without departing from the spiritand scope of the invention.

1. -21. (canceled)
 22. A carrier composition for delivery of abiologically active compound, the composition comprising a phosphatecompound of an electron transfer agent and a polar protic solventselected from the group consisting of acyclic alcohols, alkyl esters,ketones and nitriles, wherein the phosphate compound of an electrontransfer agent is a mixture of a mono-(tocopheryl) phosphate to adi-(tocopheryl) phosphate, and wherein the polar protic solventconcentration is within the range of about 60% w/w to about 90% w/w ofthe total concentration of the carrier composition.
 23. The carriercomposition of claim 22, wherein the polar protic solvent concentrationis within the range of about 65% w/w to about 85% w/w.
 24. The carriercomposition of claim 22, wherein the polar protic solvent concentrationis within the range of about 70% w/w to about 80% w/w.
 25. The carriercomposition of claim 22, wherein the polar protic solvent is an acyclicalcohol selected from the group consisting of ethanol, n-propanol,isopropanol, propylene glycol, polyethylene glycol, and diethyleneglycol monoethylether.
 26. The carrier composition of claim 22, whereinthe polar protic solvent is a ketone selected from the group consistingof methyl isobutyl ketone and acetone.
 27. The carrier composition ofclaim 22, wherein the polar protic solvent is acetonitrile.
 28. Thecarrier composition of claim 22, wherein the mixture of themono-(tocopheryl) phosphate and the di-(tocopheryl) phosphate is in aratio within the range of about 4:1 to about 1:4.
 29. The carriercomposition of claim 22, wherein the mixture of the mono-(tocopheryl)phosphate and the di-(tocopheryl) phosphate is in a ratio within therange of about 6:4 to about 8:2.
 30. The carrier composition of claim22, wherein the phosphate compound of an electron transfer agent ispresent in an amount within the range of about 0.01% w/w to about 10%w/w of the total concentration of the carrier composition.
 31. Thecarrier composition of claim 22, wherein the phosphate compound of anelectron transfer agent is present in an amount within the range ofabout 0.01% w/w to about 5% w/w of the total concentration of thecarrier composition.
 32. The carrier composition of claim 22, whereinthe phosphate compound of an electron transfer agent is present in anamount within the range of about 0.01% w/w to about 2% w/w of the totalconcentration of the carrier composition.
 33. A process for thepreparation of a carrier composition of claim 22 comprising a step ofcombining the phosphate compound of the electron transfer agent and thepolar protic solvent until complete homogenisation is achieved.
 34. Aformulation comprising a carrier composition of claim 22 and abiologically active compound.
 35. The formulation of claim 34, whereinthe biologically active compound is lipophilic having a log P valuewithin the range of about 1 to about
 5. 36. The formulation of claim 34,wherein the biologically active compound is present in an amount of upto about 30% w/w of the total concentration of the carrier composition.37. The formulation of claim 34, wherein the biologically activecompound is selected from the group consisting of lidocaine, diclofenac,ketorolac, prilocaine, halobetasol, hydrocortisol, and combinationsthereof.
 38. The formulation of claim 37, wherein the biologicallyactive compound is present in an amount of up to 5% w/w of the totalconcentration of the carrier composition.
 39. A method for treating asubject for a pathological condition which comprises administering aneffective amount of a biologically active compound that will treat thepathological condition to a subject in need thereof, wherein thebiologically active compound is formulated in a carrier composition ofclaim 22.